Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin
Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin
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DOI：
10.1038/labinvest.3700192
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发表时间：
2005-01-01
影响因子：
5
通讯作者：
Bosserhoff, AK
中科院分区：
文献类型：
--
作者：
Bataille, F;Rogler, G;Bosserhoff, AK
甲基硫代腺苷磷酸化酶（MTAP）是一种广泛表达的管家基因，在生化补救过程中起重要作用。MTAP基因位于人类染色体区域9 p21，这是一个经常在癌症中缺失的区域。最近，包括我们自己的几个小组已经表明，MTAP作为一个肿瘤抑制基因。本研究的目的是分析MTAP在结肠癌和正常结肠上皮中的作用及其基因表达调控。为了检测MTAP RNA和蛋白的表达，我们通过RT-PCR和免疫印迹筛选了6个结肠癌细胞系和人原代结肠上皮细胞。MTAP的表达在体内证实了正常结肠组织的免疫组化染色相比，腺瘤和结肠癌。有趣的是，我们发现MTAP mRNA和蛋白在结肠癌细胞系中有强表达，但在结肠上皮细胞中没有表达。为了分析MTAP表达的调节，进行启动子研究，并揭示了LEF/TCF/β-连环蛋白对MTAP表达的控制。此外，我们证明了MTAP蛋白表达与肿瘤进展之间的显着相关性，因为MTAP蛋白染色的强度从正常组织到癌组织增加。此外，最近假设的MTAP活性和干扰素（IFN）敏感性之间的关联在结肠上皮细胞中得到证实，与癌细胞系相反，结肠上皮细胞对IFN-γ的反应很小。总之，这些数据首次表明MTAP在正常人结肠上皮中不表达，但在结肠癌中强烈上调。这一发现可能对正常结肠上皮的稳态和结肠癌的潜在治疗具有临床意义。
Methylthioadenosine phosphorylase (MTAP) is known as a ubiquitously expressed house keeping gene important in biochemical salvage processes. The MTAP gene is localized on the human chromosomal region 9p21, a region often deleted in cancer. Recently, several groups including our own have shown that MTAP serves as a tumour suppressor gene. The aim of this study was to analyse the role of MTAP in colon carcinoma and normal colon epithelium and the regulation of gene expression. To examine MTAP RNA and protein expression, we screened six colon carcinoma cell lines and human primary colon epithelial cells by RT-PCR and immunoblotting. MTAP expression was confirmed in vivo by immunohistochemical staining of normal colon tissue compared to adenoma and colon carcinoma. Interestingly, we found strong MTAP mRNA and protein expression by colon carcinoma cell lines but no expression by colonic epithelial cells. To analyse the regulation of MTAP expression, promoter studies were performed and revealed control of MTAP expression by LEF/TCF/beta-catenin. Furthermore, we demonstrated a significant correlation between MTAP protein expression and tumour progression as the intensity of MTAP protein staining increased from normal tissue to carcinoma. In addition, the recently postulated association between MTAP activity and interferon (IFN) sensitivity was confirmed in colon epithelial cells showing only little response to IFN-gamma, in contrast to the carcinoma cell lines. In summary, these data indicate for the first time that MTAP is not expressed in normal human colonic epithelium but is strongly upregulated in colon carcinoma. This finding may be of clinical significance concerning the homeostasis of normal colon epithelium and potential treatment of colon carcinoma.